Project Summary/Abstract The long-term objective of this research is to enable more affordable and shorter duration clinical trials, thereby facilitating the introduction of effective disease modifying therapies for knee osteoarthritis (OA). OA affects over 27 million Americans, afflicting them with pain, substantial mobility limitations, and large health care expenditures. There are gaps in our ability to predict and detect progression, limiting the potential to forestall this prevalent disease. The critical barriers to determining prognosis and longitudinally monitoring knee OA are the poor sensitivity and responsiveness of radiographs, the most common means of evaluating knee OA. At times, these limitations have made advancement of novel treatments prohibitively expensive, through necessitating large sample sizes and long durations of follow-up for clinical studies. Our preliminary studies established the feasibility of detecting key knee OA features accurately and reliably with standing CT (SCT) imaging. In the proposed project, we will establish the performance of more useful biomarkers for OA than are available with radiographs. We propose to address the remaining steps necessary to begin qualification of these SCT-based OA biomarkers. Aim 1 is to determine the responsiveness of SCT biomarkers for detecting knee OA progression, and to establish concurrent validity through comparison with worsening of cartilage on MRI. Aim 2 is to quantify the added prognostic value of more sensitive detection of meniscal extrusion for prediction of rapid worsening of cartilage lesions and knee pain. Achieving these aims will be transformative; introducing more sensitive and responsive biomarkers for assessing OA, without significantly increasing the cost, time or radiation exposure. The ability to detect structural changes in bone and menisci earlier in the disease process could accelerate scientific progress and clinical care. The enhanced performance could identify stages when patients are most likely to respond to interventions. The expected product will be immediate delivery of substantially improved biomarkers for detection and longitudinal evaluation of OA, that could be deployed in clinical trials, using a compact scanner with the same Relative Radiation Level as radiographs. The enhanced ability to predict and measure OA progression will address critical barriers to progress in OA research and patient care by enabling more efficient assessment of therapeutic efficacy. Designation of OA as a serious disease is opening expedited pathways to approval of OA therapies, making this research timely. The long-term impact of this project will be a potential shift in clinical trials and care? replacement of radiographs for monitoring of knee OA. This research will catalyze the ability to predict and monitor knee OA worsening, enabling more rapid development of therapies by reducing the required sample sizes, duration and costs of clinical trials, thereby powerfully influencing prevention and treatment.